Project Summary Malaria remains the leading cause of parasite driven death worldwide. In 2015 alone, the WHO reported ~200 million cases and ~ half a million deaths from progression to the highly inflammatory disease state, severe malaria. Yet the immune cells and inflammatory factors that trigger death in infected hosts are not well understood. Using Plasmodium yoelii (Py) YM as a murine model of lethal blood stage infection, we found that type I IFN plays a key role in promoting fatal disease. We showed that during the acute phase of Py YM infection, plasmacytoid dendritic cells (pDCs) are the predominant source of systemic type I IFN. Importantly, we revealed that robust production of type I IFN by pDCs requires the presence of CD169+ macrophages (CD169+ MP) and the adapter molecule for cytoplasmic DNA sensing?STING (stimulator of interferon genes)?in the radio-resistant compartment to which MP belong. In addition, we found that pDCs arrest and cluster around CD169+ MPs in the bone marrow of Py YM-infected mice using intravital two-photon microscopy. We thus hypothesize that CD169+ MPs provide contact dependent signals to pDCs during infection, ?priming? them to produce large quantities of type I IFN. We are investigating the mechanisms that govern MP/pDC interactions and the nature of the STING-dependent signals that CD169+ MPs provide to pDCs. We believe this work will help elucidate how pDCs are activated in severe malaria, which could serve as the basis for tuning of type I IFN production in malaria and potentially other type I IFN driven diseases.